Bipolar depression, the depressive phase of bipolar disorder (BD), is a major therapeutic challenge and frequent cause of chronic impairment. Patients suffering from bipolar depression are often non-responsive to various therapeutic interventions. Abnormalities in fronto-limbic brain (FLB) mechanisms could account for their pathophysiology and relate to treatment response. We propose to test specific hypotheses about the involvement of FLB circuits in bipolar depression in BD type 1patients, and the relationship of FLB abnormalities to symptom remission and treatment response to mood stabilizing agents. Study Design and Methods: In vivo brain imaging methods (magnetic resonance imaging, MRI, and MRspectroscopy, MRS) will be utilized to measure and compare regional brain volumes and regional levels of Nacetyl Aspartate (NAA), a non-specific marker of neuronal viability and function, in prefrontal cortex and medial temporal lobe regions. 90 untreated depressed DSM-IV BD type I patients will undergo MRI and MRS scans at entry to the study, and after 4 and 16 weeks of medication treatment. 60 matched healthy controls will undergo MRS scan at entry, of which 20 will repeat these measures at weeks 4 and 16. The BD patients will be stratified into 3 groups, based on their responsiveness to treatments (>50% improvement in HAMD-21 item scores) during the 16-week period: (i) those who improve following 4 weeks of monotherapy with lithium, and remain improved until the end of the 16-week follow-up period, (ii) monotherapy non-responders who subsequently are responsive to an additional 12 weeks of combination treatment with lamotrigine and lithium, and (iii) patients with bipolar depression who do not respond to either monotherapy or combination therapy. Specific Hypotheses: I: Bipolar depression arises from impairment in neuronal survival in FLB circuits. II: Treatment with a mood-stabilizing agent has detectable effects of ameliorating or reversing prefrontal cortex (PFC) abnormalities. III: Amygdala abnormalities are related to decreased PFC inhibitory drive. IV: Therapeutic response to mood stabilizing agents is related to amelioration or reversal of FLB abnormalities.